P-Cadherin
Classical cadherins represent a family of cell adhesion molecules expressed in adherens-type junctions that mediate calcium-dependent cell-to-cell contacts. Placental cadherin (P-cadherin; also known as cadherin 3, type 1 or “CDH3”) has restricted expression in normal tissues but is known to be expressed in undifferentiated or under-differentiated cell types of several tissues, including the basal epithelial cells of the skin, esophagus, lung and oral cavity. (see, e.g., Albergaria et al., Int. J. Dev. Biol. 55:811-822 (2011)).
The structure of P-cadherin consists of 3 distinct domains: an extracellular domain (ECD) containing five cadherin repeats in tandem, a transmembrane domain, and an intracellular tail containing a catenin binding domain. The ECD mediates both cis- and trans interactions between multiple P-cadherin molecules, while the catenin binding domain links P-cadherin to proteins such as p120 catenin and consequently, cellular cytoskeletal elements. (see, e.g., Wu et al., PNAS 107:17592-7 (2010).
P-Cadherin and Cancer
P-cadherin (also referred to as “Pcad” “PCad” “P-Cad, or CDH3), is also known to be overexpressed in a number of malignant tumors, including breast, gastric, endometrial, head and neck, and colorectal cancer, among others. The overexpression of P-cadherin in some breast, endometrial, ovarian, colorectal and bladder tumors has also been correlated with a worse prognosis compared to cases where P-cadherin expression levels are low or absent. In breast cancer, P-cadherin is frequently overexpressed in high grade invasive carcinomas and is a reliable marker of basal-like tumors. (see, e.g., Paredes et al., Br. Can. Res. 9:214-226 (2007); Sanders et al., Int. J. Can. 79:573-579 (1998); Albergaria et al., Int. J. Dev. Biol. 55:811-822 (2011); Sousa et al., Histol. Histopathol. 25:963-975 (2010))
In certain cancer types, such as breast and ovarian cancer, P-cadherin is known to promote tumor cell motility, invasiveness and metastasis. (see, e.g., Cheung et al., Oncogene 30:2964-74 (2011); Ribeiro et al, Oncogene 29 :392-402 (2010)).
Numerous cancer-relevant processes are known to promote the expression of P-cadherin mRNA and protein. Inactivation of the tumor suppressor BRCA1 through either mutation or loss of expression has been associated with increased P-cadherin expression in both breast cancer cell lines and patient specimens. The transcription factor C-EBPβ and the anti-estrogen ICI182780 (fulvestrant) are also known to disregulate P-cadherin expression and induce its upregulation in tumor cells, as is hypomethylation of the CDH3 promoter via other processes. In alveolar rhabdomyosarcoma, the chimeric oncogenic transcription factors PAX3-FOXOA1 and PAX7-FOXOA1 (resulting from translocations) directly induce P-cadherin expression, resulting in increased tumor aggressiveness. (see e.g. Albergaria et al., Int. J. Dev. Biol. 55:811-822 (2011); Thuault et al., Oncogene 15:1474-86 (2012); Ames et al., Clin. Can. Res. 11; 4003-11 (2005); Gorski et al., Br. Can. Res. Treat. 122:721-31 (2010); Paredes et al., Clin. Can. Res. 11:5869-5877 (2005); Albergaria et al., Human Mol. Gen. 19:2554-2566 (2010).
Antibody Drug Conjugates
Antibody drug conjugates (“ADCs”) have been used for the local delivery of cytotoxic agents in the treatment of cancer (see e.g., Lambert, Curr. Opinion In Pharmacology 5:543-549, 2005). ADCs allow targeted delivery of the drug moiety where maximum efficacy with minimal toxicity may be achieved. As more ADCs show promising clinical results, there is an increased need to develop new therapeutics for cancer therapy. Moreover, not all attempts to make therapeutically effective ADCs to known cancer targets have been successful. Examples of factors that can effect therapeutic effectiveness of ADCs include affinity, ability of an antibody to conjugate, the cleavability or stability of the linker; stability of the antibody-drug conjugate, the tendency of an antibody drug conjugate to aggregate, and the ratio of the drug/payload molecules that conjugate to each antibody (“DAR” or “drug antibody ratio”).
Aggregation and lack of stability can increase the possibility of adverse reactions to antibody drug conjugates in a clinical setting, reduce efficacy, as well as add to the cost of making ADCS.
Therefore there is a need for therapeutically effective ADC molecules.